Given that existing pain treatments (which primarily target neurons) reduce pain by only around 25-40% in less than half of the 15 million patients suffering from chronic neuropathic pain in the US, there is a need for new methods to identify and investigate pain-related cellular processes beyond only neuronal function.
Of the pain drugs currently available, opioid analgesics are the gold standard despite their addiction liabilities. A biomarker for neuropathic pain does not exist despite the need to objectively identify those individuals in need of treatment.
Further, the neuron centered view of pain processing is changing, and non-neuronal targets are emerging, including glial cells and leukocytes that enrich the spinal cord and other central nervous system sites (CNS) critical for pathological pain signaling. Thus, it is possible that by targeting non-neuronal signaling mechanisms, a novel biomarker to identify neuropathic pain may emerge.
Indeed, upon strong pain-related neuronal activation, spinal cord glia contribute to persistent pathological pain by responding to and releasing proinflammatory cytokines like IL-1β & TNF-α as well as the activity of matrix metalloproteinase (MMP) enzymes [Dev 2010]. Leukocytes may additionally contribute to ongoing pathological pain by releasing and responding to IL-1β and TNF-α, with an additional contribution of MMPs. However, MMPs not only contribute to the neuroinflammation, but may be directly involved in pain-associated nerve damage.
There has been an increasing interest in matrix metalloproteinase (MMP) enzyme biosensing activity as a biomarker for neurological diseases. Several studies on MMP activity in patients with neurological diseases generally indicate abnormal MMP activity in the serum and CSF. In specific, patients with amyotrophic lateral sclerosis (ALS) statistically show 3 times lower MMP-9 activity in the CSF and 2 times higher MMP-9 activity in the serum, in comparison to healthy controls [Niebroj-Dobosz 2010]. Furthermore, it was statistically shown that patients with HIV [Liuzzi 2000] and multiple sclerosis [Leppert 1998] have increased MMP-9 activity, while patients with Alzheimer's show no abnormal MMP-9 activity at all [Adair 2004]. Most of these findings were done via gel electrophoresis; a multistep assay process. A simpler and highly effective sensing method for indicating these findings could have a positive impact on clinical treatment.
MMPs are zinc dependent endopeptidases which can bind to specific non-terminal amino acids in peptides with specific amino acid sequences. Active MMPs form bonds to amino acid residues at the active site of the MMP, which consists of a highly reactive zinc ion. After binding to a peptide, MMPs will catalyze hydrolysis and break a bond between two amino acid residues in a peptide. MMPs are initially synthesized as inactive by the body's immune system, but become active due to injury, inflammation, or the presence of other proteinases, foreign bodies, and pathogens. Specifically, MMPS are made active by the removal of a peptide blocking the active region due to a bond between the Zn2+ ion and the thiol group in the cysteine amino acid residue.
The previous findings reported in literature relating neurological diseases to MMPs are a good indication of their potential as a biomarker. However, in vivo biosensing of MMP activity remains largely unexplored.